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Background: Efgartigimod, a human immunoglobulin (Ig)G1 antibody Fc fragment, blocks the neonatal Fc receptor, reducing IgGs involved in chronic inflammatory demyelinating polyneuropathy (CIDP). The multi-stage, double-blinded, placebo-controlled ADHERE (NCT04281472) and open-label extension ADHERE+ (NCT04280718) trials (interim analysis cutoff: February 16, 2024) assessed efgartigimod PH20 SC in participants with CIDP. Methods: Participants with active CIDP received open-label, weekly efgartigimod PH20 SC 1000 mg during ≤12-week run-in (stage-A). Responders were randomized (1:1) to efgartigimod or placebo for ≤48 weeks (stage-B). Participants with clinical deterioration in stage-B or who completed ADHERE entered ADHERE+. Week 36 changes from run-in baseline (CFB) in adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT), Inflammatory Rasch-built Overall Disability Scale (I-RODS), and grip strength scores were evaluated. Results: Of 322 stage-A participants, 221 were randomized and treated in stage-B, and 99% entered ADHERE+. Mean CFB (SE) in aINCAT, I-RODS, and grip strength scores were -1.2 (0.15) and 8.8 (1.46) and 17.5 (2.02), respectively, at ADHERE+ Week 36 (N=150). Half the participants with clinical deterioration during ADHERE stage-B restabilized on efgartigimod from ADHERE+ Week 4. Conclusions: Interim results from ADHERE+ indicate long-term effectiveness of efgartigimod PH20 SC in clinical outcomes in participants with CIDP.
Background: Efgartigimod, a human immunoglobulin (Ig)G1 antibody Fc fragment, blocks the neonatal Fc receptor, reducing IgGs involved in chronic inflammatory demyelinating polyneuropathy (CIDP), a rare, progressive, immune-mediated disease that can lead to irreversible disability. The multi-stage, double-blinded, placebo-controlled ADHERE (NCT04281472) trial assessed efgartigimod PH20 SC in participants with CIDP. Methods: Participants with active CIDP received open-label, weekly efgartigimod PH20 SC 1000 mg during ≤12-week run-in (stage-A). Responders were randomized (1:1) to weekly efgartigimod or placebo for ≤48 weeks (stage-B). This posthoc analysis evaluated changes from run-in baseline (study enrollment) to stage-B last assessment and items of the Inflammatory Rasch-built Overall Disability Scale (I-RODS). Results: Of 322 participants who entered stage-A, 221 were randomized and treated in stage-B, and 191/221 had data for run-in baseline and post–stage-B timepoints. Mean (SE) I-RODS change at stage-B last assessment vs run-in baseline was 5.7 (1.88) and -4.9 (1.82) in participants randomized to efgartigimod and placebo, respectively. 37/97 (38.1%) and 24/92 (26.1%) participants randomized to efgartigimod and placebo, respectively, experienced ≥4-point improvements in I-RODS score. Efgartigimod-treated participants improved ≥1 point in I-RODS items of clinical interest. Conclusions: Participants who received efgartigimod in stage-B experienced improvements in I-RODS score from study enrollment to stage-B last assessment.
The First Large Absorption Survey in H i (FLASH) is a large-area radio survey for neutral hydrogen in and around galaxies in the intermediate redshift range $0.4\lt z\lt1.0$, using the 21-cm H i absorption line as a probe of cold neutral gas. The survey uses the ASKAP radio telescope and will cover 24,000 deg$^2$ of sky over the next five years. FLASH breaks new ground in two ways – it is the first large H i absorption survey to be carried out without any optical preselection of targets, and we use an automated Bayesian line-finding tool to search through large datasets and assign a statistical significance to potential line detections. Two Pilot Surveys, covering around 3000 deg$^2$ of sky, were carried out in 2019-22 to test and verify the strategy for the full FLASH survey. The processed data products from these Pilot Surveys (spectral-line cubes, continuum images, and catalogues) are public and available online. In this paper, we describe the FLASH spectral-line and continuum data products and discuss the quality of the H i spectra and the completeness of our automated line search. Finally, we present a set of 30 new H i absorption lines that were robustly detected in the Pilot Surveys, almost doubling the number of known H i absorption systems at $0.4\lt z\lt1$. The detected lines span a wide range in H i optical depth, including three lines with a peak optical depth $\tau\gt1$, and appear to be a mixture of intervening and associated systems. Interestingly, around two-thirds of the lines found in this untargeted sample are detected against sources with a peaked-spectrum radio continuum, which are only a minor (5–20%) fraction of the overall radio-source population. The detection rate for H i absorption lines in the Pilot Surveys (0.3 to 0.5 lines per 40 deg$^2$ ASKAP field) is a factor of two below the expected value. One possible reason for this is the presence of a range of spectral-line artefacts in the Pilot Survey data that have now been mitigated and are not expected to recur in the full FLASH survey. A future paper in this series will discuss the host galaxies of the H i absorption systems identified here.
The stars of the Milky Way carry the chemical history of our Galaxy in their atmospheres as they journey through its vast expanse. Like barcodes, we can extract the chemical fingerprints of stars from high-resolution spectroscopy. The fourth data release (DR4) of the Galactic Archaeology with HERMES (GALAH) Survey, based on a decade of observations, provides the chemical abundances of up to 32 elements for 917 588 stars that also have exquisite astrometric data from the Gaia satellite. For the first time, these elements include life-essential nitrogen to complement carbon, and oxygen as well as more measurements of rare-earth elements critical to modern-life electronics, offering unparalleled insights into the chemical composition of the Milky Way. For this release, we use neural networks to simultaneously fit stellar parameters and abundances across the whole wavelength range, leveraging synthetic grids computed with Spectroscopy Made Easy. These grids account for atomic line formation in non-local thermodynamic equilibrium for 14 elements. In a two-iteration process, we first fit stellar labels to all 1 085 520 spectra, then co-add repeated observations and refine these labels using astrometric data from Gaia and 2MASS photometry, improving the accuracy and precision of stellar parameters and abundances. Our validation thoroughly assesses the reliability of spectroscopic measurements and highlights key caveats. GALAH DR4 represents yet another milestone in Galactic archaeology, combining detailed chemical compositions from multiple nucleosynthetic channels with kinematic information and age estimates. The resulting dataset, covering nearly a million stars, opens new avenues for understanding not only the chemical and dynamical history of the Milky Way but also the broader questions of the origin of elements and the evolution of planets, stars, and galaxies.
Although dementia is a terminal condition, palliation can be a challenge for clinical services. As dementia progresses, people frequently develop behavioural and psychological symptoms, sometimes so severe they require care in specialist dementia mental health wards. Although these are often a marker of late disease, there has been little research on the mortality of people admitted to these wards.
Aims
We sought to describe the mortality of this group, both on-ward and after discharge, and to investigate clinical features predicting 1-year mortality.
Method
First, we conducted a retrospective analysis of 576 people with dementia admitted to the Cambridgeshire and Peterborough National Health Service (NHS) Foundation Trust dementia wards over an 8-year period. We attempted to identify predictors of mortality and build predictive machine learning models. To investigate deaths occurring during admission, we conducted a second analysis as a retrospective service evaluation involving mental health wards for people with dementia at four NHS trusts, including 1976 admissions over 7 years.
Results
Survival following admission showed high variability, with a median of 1201 days (3.3 years). We were not able to accurately predict those at high risk of death from clinical data. We found that on-ward mortality remains rare but had increased from 3 deaths per year in 2013 to 13 in 2019.
Conclusions
We suggest that arrangements to ensure effective palliation are available on all such wards. It is not clear where discussions around end-of-life care are best placed in the dementia pathway, but we suggest it should be considered at admission.
Having a relapse of schizophrenia or recurrent psychosis is feared by patients, can cause social and personal disruption and has been suggested to cause long-term deterioration, possibly because of a toxic biological process.
Aims
To assess whether relapse affected the social and clinical outcomes of people enrolled in a 24-month randomised controlled trial of antipsychotic medication dose reduction versus maintenance treatment.
Methods
The trial involved participants with a diagnosis of schizophrenia or recurrent, non-affective psychosis. Relapse was defined as admission to hospital or significant deterioration (assessed by a blinded end-point committee). We analysed the relationship between relapse during the trial and social functioning, quality of life, symptom scores (Positive and Negative Syndrome Scale) and rates of being in employment, education or training at 24-month follow-up. We also analysed changes in these measures during the trial among those who relapsed and those who did not. Sensitivity analyses were conducted examining the effects of ‘severe’ relapse (i.e. admission to hospital).
Results
During the course of the trial, 82 out of 253 participants relapsed. There was no evidence for a difference between those who relapsed and those who did not on changes in social functioning, quality of life, symptom scores or overall employment rates between baseline and 24-month follow-up. Those who relapsed showed no change in their social functioning or quality of life, and a slight improvement in symptoms compared to baseline. They were more likely than those who did not relapse to have had a change in their employment status (mostly moving out of employment, education or training), although numbers changing status were small. Sensitivity analyses showed the same results for those who experienced a ‘severe’ relapse.
Conclusions
Our data provide little evidence that relapse has a detrimental effect in the long term in people with schizophrenia and recurrent psychosis.
Underrepresentation of diverse populations in medical research undermines generalizability, exacerbates health disparities, and erodes trust in research institutions. This study aimed to identify a suitable survey instrument to measure trust in medical research among Black and Latino communities in Baltimore, Maryland.
Methods:
Based on a literature review, a committee selected two validated instruments for community evaluation: Perceptions of Research Trustworthiness (PoRT) and Trust in Medical Researchers (TiMRs). Both were translated into Spanish through a standardized process. Thirty-four individuals participated in four focus groups (two in English, two in Spanish). Participants reviewed and provided feedback on the instruments’ relevance and clarity. Discussions were recorded, transcribed, and analyzed thematically.
Results:
Initial reactions to the instruments were mixed. While 68% found TiMR easier to complete, 74% preferred PoRT. Key discussion themes included the relevance of the instrument for measuring trust, clarity of the questions, and concerns about reinforcing negative perceptions of research. Participants felt that PoRT better aligned with the research goal of measuring community trust in research, though TiMR was seen as easier to understand. Despite PoRT’s lower reading level, some items were found to be more confusing than TiMR items.
Conclusion:
Community feedback highlighted the need to differentiate trust in medical research, researchers, and institutions. While PoRT and TiMR are acceptable instruments for measuring trust in medical research, refinement of both may be beneficial. Development and validation of instruments in multiple languages is needed to assess community trust in research and inform strategies to improve diverse participation in research.
Because pediatric anxiety disorders precede the onset of many other problems, successful prediction of response to the first-line treatment, cognitive-behavioral therapy (CBT), could have a major impact. This study evaluates whether structural and resting-state functional magnetic resonance imaging can predict post-CBT anxiety symptoms.
Methods
Two datasets were studied: (A) one consisted of n = 54 subjects with an anxiety diagnosis, who received 12 weeks of CBT, and (B) one consisted of n = 15 subjects treated for 8 weeks. Connectome predictive modeling (CPM) was used to predict treatment response, as assessed with the PARS. The main analysis included network edges positively correlated with treatment outcome and age, sex, and baseline anxiety severity as predictors. Results from alternative models and analyses are also presented. Model assessments utilized 1000 bootstraps, resulting in a 95% CI for R2, r, and mean absolute error (MAE).
Results
The main model showed a MAE of approximately 3.5 (95% CI: [3.1–3.8]) points, an R2 of 0.08 [−0.14–0.26], and an r of 0.38 [0.24–0.511]. When testing this model in the left-out sample (B), the results were similar, with an MAE of 3.4 [2.8–4.7], R2−0.65 [−2.29–0.16], and r of 0.4 [0.24–0.54]. The anatomical metrics showed a similar pattern, where models rendered overall low R2.
Conclusions
The analysis showed that models based on earlier promising results failed to predict clinical outcomes. Despite the small sample size, this study does not support the extensive use of CPM to predict outcomes in pediatric anxiety.
We revisit viscoelastic Kolmogorov flow to show that the elastic linear instability of an Oldroyd-B fluid at vanishing Reynolds numbers ($Re$) found by Boffetta et al. (J. Fluid Mech., vol. 523, 2005, pp. 161–170) is the same ‘centre-mode’ instability found at much higher $Re$ by Garg et al. (Phys. Rev. Lett., vol. 121, 2018, 024502) in a pipe and by Khalid et al. (J. Fluid Mech., vol. 915, 2021, A43) in a channel. In contrast to these wall-bounded flows, the centre-mode instability exists even when the solvent viscosity vanishes (e.g. it exists in the upper-convective Maxwell limit with $Re=0$). Floquet analysis reveals that the preferred centre-mode instability almost always has a wavelength twice that of the forcing. All elastic instabilities give rise to familiar ‘arrowheads’ (Page et al., Phys. Rev. Lett., vol. 125, 2020, 154501) which in sufficiently large domains and at sufficient Weissenberg number ($W$) interact chaotically in two dimensions to give elastic turbulence via a bursting scenario. Finally, it is found that the $k^{-4}$ scaling of the kinetic energy spectrum seen in this two-dimensional elastic turbulence is already contained within the component arrowhead structures.
Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
Fifty-three tests designed to measure aspects of creative thinking were administered to 410 air cadets and student officers. The scores were intercorrelated and 16 factors were extracted. Orthogonal rotations resulted in 14 identifiable factors, a doublet, and a residual. Nine previously identified factors were: verbal comprehension, numerical facility, perceptual speed, visualization, general reasoning, word fluency, associational fluency, ideational fluency, and a factor combining Thurstone's closure I and II. Five new factors were identified as originality, redefinition, adaptive flexibility, spontaneous flexibility, and sensitivity to problems.
Maximum likelihood factor analysis provides an effective method for estimation of factor matrices and a useful test statistic in the likelihood ratio for rejection of overly simple factor models. A reliability coefficient is proposed to indicate quality of representation of interrelations among attributes in a battery by a maximum likelihood factor analysis. Usually, for a large sample of individuals or objects, the likelihood ratio statistic could indicate that an otherwise acceptable factor model does not exactly represent the interrelations among the attributes for a population. The reliability coefficient could indicate a very close representation in this case and be a better indication as to whether to accept or reject the factor solution.
In many applications, it is desirable to estimate binomial proportions in m groups where it is anticipated that these proportions are similar but not identical. Following a general approach due to Lindley, a Bayesian Model II aposteriori modal estimate is derived that estimates the inverse sine transform of each proportion by a weighted average of the inverse sine transform of the observed proportion in the individual group and the average of the estimated values. Comparison with a classical method due to Jackson spotlights some desirable features of Model II analyses. The simplicity of the present formulation makes it possible to study the behavior of the Bayesian Model II approach more closely than in more complex formulations. Also, it is possible to estimate the amount of gain afforded by the Model II analyses.
A Bayesian Model II approach to the estimation of proportions in m groups (discussed by Novick, Lewis, and Jackson) is extended to obtain posterior marginal distributions for the proportions. It is anticipated that these will be useful in applications (such as Individually Prescribed Instruction) where decisions are to be made separately for each proportion, rather than jointly for the set of proportions. In addition, the approach is extended to allow greater use of prior information than previously and the specification of this prior information is discussed.
Following a general approach due to Guttman, coefficientα is rederived as a lower bound on the reliability of a test. A necessary and sufficient condition under which equality is attained in this inequality and hence that α is equal to the reliability of the test is derived and shown to be closely related to the recent redefinition of the concept of parallel measurements due to Novick. This condition is then also shown to be closely related to the unit rank assumption originally adopted by Kuder and Richardson in the derivation of their formula 20. The assumption later adopted by Jackson and Ferguson and the one adopted by Gulliksen are shown to be related to the necessary and sufficient condition derived here. It is then pointed out that the statement that “coefficient α is equal to the mean of the split-half reliabilities” is true only under the restricted condition assumed by Cronbach in the body of his derivation of this result. Finally some limitations on the uses of any function of α as a measure of internal consistency are noted.
Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.
Methods
We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.
Results
The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).
Conclusion
The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.
Aluminum-substituted hematites (Fe2−xAlxO3) were synthesized from Fe-Al coprecipitates at pH 5.5, 7.0, and in 10−1, 10−2, and 10−2 M KOH at 70°C. As little as 1 mole % Al suppressed goethite completely at pH 7 whereas in KOH higher Al concentrations were necessary. Al substitution as determined chemically and by XRD line shift was related to Al addition up to a maximum of 16–17 mole %. The relationship between the crystallographic a0 parameter and Al substitution deviated from the Vegard rule. At low substitution crystallinity of the hematites was improved whereas higher substitution impeded crystal growth in the crystallographic z-direction as indicated by differential XRD line broadening. At still higher Al addition crystal growth was strongly retarded. The initial Al-Fe coprecipitate behaved differently from a mechanical mixture of the respective “hydroxides” and was, therefore, considered an aluminous ferrihydrite.
Background: Efgartigimod, a human immunoglobulin G (IgG)1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing pathogenic IgG autoantibody levels. ADHERE assessed the efficacy and safety of efgartigimod PH20 subcutaneous (SC; co-formulated with recombinant human hyaluronidase PH20) in chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: ADHERE enrolled participants with CIDP (treatment naive or on standard treatments withdrawn during run-in period) and consisted of open-label Stage A (efgartigimod PH20 SC once weekly [QW]), and randomized (1:1) Stage B (efgartigimod or placebo QW). Primary outcomes were clinical improvement (assessed with aINCAT, I-RODS, or mean grip strength; Stage A) and time to first aINCAT score deterioration (relapse; Stage B). Secondary outcomes included treatment-emergent adverse events (TEAEs) incidence. Results: 322 participants entered Stage A. 214 (66.5%) were considered responders, randomized, and treated in Stage B. Efgartigimod significantly reduced the risk of relapse (HR: 0.394; 95% CI: 0.25–0.61) versus placebo (p=0.000039). Reduced risk of relapse occurred in participants receiving corticosteroids, intravenous or SC immunoglobulin, or no treatment before study entry. Most TEAEs were mild to moderate; 3 deaths occurred, none related to efgartigimod. Conclusions: Participants treated with efgartigimod PH20 SC maintained a clinical response and remained relapse-free longer than those treated with placebo.